The Sentinel Node:
1) Neoadjuvant Chemotherapy
2) Ipsilateral Breast Cancer Recurrence
EJW 2006
Basic Concepts
Sentinel node (SLN) “biopsy” has been demonstrated to be remarkably accurate in evaluating the axilla for nodal metastases. It is at least as good for axillary assessment as axillary lymph node dissection (ALND) and probably superior.[1] In the past, standard pathology evaluation of ALND nodes resulted in a 7-20% false negative result when re-evaluated by serial sectioning.[2,3] SLN evaluation yields a 5-6% false negative rate. In “early” breast cancer, and even after neoadjuvant chemotherapy, studies show that when the sentinel node is positive it is the only positive lymph node about 50% of the time.[4,5] That fact may explain why standard evaluation tends to miss more positive axillary states than the more intensive study of the SLN.
Additionally, long term follow-up of sentinel node negative patients with no ALND has recurrence rates of 1.5% or less.[6] From an axillary risk standpoint, even with a positive sentinel node and standard BCT Rx, axillary recurrence is rare.[7,8]
Survival after negative SLN treated with adjuvant Rx is superior to historical NSABP series with node negative standard ALND with adjuvant Rx, suggesting that missed positive nodes in old studies lead to errors in stage and prognosis. Improved data on modern SLN studies leads to more accurate classification.[9]
Moreover, there is abundant data from randomized studies suggesting that axillary node dissection, per se, provides no benefit to overall survival.[10-15] This may be especially true in the setting of BCT where chemotherapy and radiation therapy functionally target any “missed” axillary disease.[16-22] The recent development of multigene assays capable of predicting pCR may further limit the need for axillary dissection to those proven to be at high risk of incomplete response.[23,24] These studies were performed on RNA obtained by FNA of the tumor.
Therefore SLN (selective sentinel-lymphadenectomy) is extraordinarily useful in obtaining needed information for treatment planning while minimizing risk and morbidity.
Sentinel node: Next Level questions
There are new settings (previously thought to be contraindications) in which sentinel node evaluation may be useful.
• Peri- neoadjuvant chemotherapy, (i.e. post or pre neoadjuvant.)
• Ipsilateral breast tumor recurrence (IBTR) with prior axillary interventions.
Post Neo-adjuvant Chemotherapy Axillary Node Issues
Neoadjuvant chemotherapy has become increasingly used in the setting of more advanced local disease. Originally used in inflammatory breast cancer, it has been recently extended to locally advanced non-inflammatory cases in the hope of reducing subsequent mortality as yet with no proof in that application. Trends suggesting benefit in overall survival were noted in nine year follow-up in the B-18 trials for pre-menopausal patients, but worsened survival was noted in post-menopausal patients, and the net effect was no overall change in survival.[25] (These issues may prove to be very different with her-2-neu positive patients treated with herceptin.)[26] Many studies show an approximate 25% complete pathologic response (cPR) to neo adjuvant chemotherapy. That response predicts for a better longterm outcome. However, recent evidence suggests that gene expression profiles of the tumor will allow accurate prediction of cPR, possibly eliminating the need for the clinical “test”.[24] Certainly a significant number of patients can be converted to BCT rather than mastectomy by neoadjuvant chemotherapy, though there can be substantial theoretical questions about this approach, (e.g., does the known increase risk for local recurrence after conversion to BCT contribute to decreased overall survival and cancel the benefit of neoadjuvant treatment?)[27-32]
With the increased frequency of neoadjuvant therapy there has not been a standard approach to the axillary nodes. It would be appropriate to consider some standards.
The fundamental question underlying this analysis will be:
“What do we want to know and why do we think we want to know it”
• Is sentinel node ID possible in this setting?
• Is the sentinel node concept meaningful in this setting? I.e. => (Will it change therapy/ Surgery, Chemo or Rad Rx?)
• Does a positive sentinel node imply additional positive nodes?
• Can ALND be avoided if SLN Negative?
• Should the approach for clinical N0 be different from N1/N2 patients?
• Should SLN BX be done pre Neoadj Rx (instead of or in addition to)
• Should a positive sentinel node in the Axillary Node Dissection Group lead to more detailed study of additional nodes? If a sentinel node is positive, added levels used to evaluate non-sentinel nodes may result in ~ 20% positive non-sentinel node? (Will evidence of additional positive nodes change Rx.)
• In ALND patients, it is the sentinel node “positive” by SLN protocol, remainder “negative” by standard protocol that may be significant. If the sentinel node is not identified the positive status may be missed, since it may be the only positive node 50% of the time. If ALND “only” without SLN ID then may miss metastases at only two levels per node. SLN the Only + node ~30-50%[33,34]
Other Issues
• Sentinel node count may be lower post neoadjuvant Rx[35]
• What is the correlation between in breast CPR and nodal CPR. Can true CPR in the axilla be based on “standard pathology” of a standard ALND?
Axillary Nodes After Neoadjuvant ChemoRx
Le Bouedec, Geissler, et al2006[36]
• 74 pts T1T2T3N0N1 POST neo
• SLN 68/74 (92%) then ALND
• Mets in 30/68 (44%) i.e. Neg 56%
• False neg 14% But if clinically neg N0 pre RX then accuracy 100% and FN 0%
• In 32 N1 patients accuracy 83% FN 25%
Reitsamer, Peintinger, et al (2003)[33]
• 30 Patients Stage II or III, Rx Neoadj Chemo
• Attempted SLN with completion ALND
• SLN 26 of 30 (86.7%) (could not ID SLN in 4 (13.3%)
• SLN accurate 25 of 26 (96.2%)
• 11 pts Neg SLN and Neg ALND
• 6 pts Pos SLN and Pos ALND
• 8 pts SLN pos and the only Pos node (~30%)
• 1 pt false-neg (1/15 = 6.7%)
Cohen, Breslin, et al (2000)[37]
• 38 pts, stage II or III treated with neoadjuvant chemo
• SLN attempted then ALND
• If SLN neg then all other nodes 3 add’l levels + IHC
• SLN ID in 31 (82%) and accurate 28 (90%)
• 3 False neg
• 4 of 20 “neg” SLN with add’l studies + for occult mets (20%)
Kinoshita, Takasugi, et al, 2006[38]
• Post neo 77 pts Stage II and III
• Clinically node neg post Rx
• SLN then ALND
• SLN ID 72 of 77 (93.5%)
• 69 of 72 accurate (95.8%)
• 3 of 27 False Neg (11%)
Mamounas, Brown et alNSABP B-27[34]
• 428 pts
• SLN then ALND
• SLN ID 89% with isotope
• +SLN the only + node in 56% (70 of 125)
• Of 218 Neg SLN nonsent + 15 => False neg 11%
Kuerer, Sahin, et al (1999)[39]
• 191 pts “cyto +” ALN => neoadj chemo
• Surgery ALND
• 43 pts ALND “neg” re-eval confirmed Neg (add’l 1112 sections/half IHC)
• =>43 of 191 “+” converted to neg (23%) by neoadj chemo
• Of those 43, 11 were N1 and 32 were N2
• If Converted to Neg: 5 yr surv = 87%
• If Residual Positive: 5 yr surv = 51%
• If Occult Positive (10%): 5 yr = 75%
• Proposed: maybe consider SLN
POST-NEO SLN / PTS / SLN ID / False Neg / SLN Accurate / SLN only+Le Bouedec
2006
SL/ALND / 74 PTs / 68
(92%) / 14%
If cN0 pre 0% / 83%
100%
Reitsamer
2003
SLN/ALND / 30 / 26
86% / 25/26
96% / 8/30
30%
Cohen
2000
SLN/ALND / 38 / 31
82% / 28/30
90%
Kinoshita
2006
SLN/ALND / 77 / 72/77
93% / 3/27
11% / 72/77
96%
B-27 / 428 / 89% / 11% / 70/125
56%
SLN before Neo adjuvant
Van Rijk, Nieweg, et al 2006[40]
• Reviewed 18 studies SLN after neoRX, SLN ID 89%, FN 10%
Then studied:
• SLN in 25 T2 preRX
• if pre SLN + then ALND after neoadj
• 10 pos SLN=>post Rx ALND=> 4 pts addl nodes pos in compl ALND
• 14 SLN Neg pts=> no completion ALND =>no recurrence 18 mo
Kahn, Sabel, et al 2005[41]
• 91 patients pre neo axillary staging
• Pre neo SLN Bx path Neg 58% (53 pts)
• Pre neo Pos by US FNA or SLN 42% (38 pts)
• These 38 pts then Neo=>then ALND
• 33 of these SLN attempted, found 32 (97%)
• 33% of these Node Negative on ALND
• Residual disease 22 patients
• “False negative” 1 pt (4.5%)
Cox,Cox, et al., 2006[16]
• 89 pts (42 palp or image+ histo proven; 47 cN0)
• 47 cN0 SLN preRX
• 82 of 89 + nodes
• 7 (8%) of 89 neg SLN=>no completion ALND (no recurrence in25 mo)
• 24 (27%) pCR axilla; 26% grp 1 and 33% grp 2
• Demonstrated improved prognosis, avoided ALND 15%, improved staging 53%
ComparisonJones, Zabicki, et al., 2005[42]
• SLN ID rates better pre than post 100% vs 80.6%
• Recommend SLN in cN0 pre Rx and question its use post neo
Proposed
• If accuracy is important to the overall treatment planning and sequencing, then pre-treatment workup requires staging the axilla. If clinically + or US + then Bx; if cN0 and US/N0 Then SLN Bx pre-treatment
• If pre-treatment SLN is negative (with good mapping and careful assessment), then leave the axilla alone post treatment.
• If pre-treatment SLN or US/FNA are positive, then post treatment ALND with SLN ID.
• If post treatment axillary status is important in defining added treatment then repeat SLN and complete ALND with additional levels in non-SLNs if the SLN is positive.
Next Question: IBTR
The increased use of breast conservation therapy will continue to increase the number of patients who present with ipsilateral “in-breast” recurrence (perhaps as high as 1-2% per year). In this setting prior axillary interventions (ALND or SLN Bx) have generally been performed. These “recurrences” represent both true recurrences (same site) and new primaries. In many of these patients the implication of node metastases, or lack thereof, should be equivalent to the original setting. If knowledge of the nodal status is therapeutically important, then reassessment is required. This may be particularly important in “late” recurrences that are more likely to be true new primaries. A number of studies have looked at the question of “repeat nodal evaluations”.
Dinan, Nagle, et al 2005[43]
• 16 pts second IBTR
• Lymphoscintigraphy pos 69%
• Ipsi ax, contra ax, supraclav (ipsi and contra)
Intra, Trifiro, et al, 2005[44]
• 79 pts recurrent disease prior SLN -
• 18 pts cN0 ~ 26 mo after initial Dx/Rx
• Pre op ID SLN 100% with lymphoscintigrapy and SLN removed average 1.3
• SLN pos in 2 patients
• At 12 mo no recurrences in pts SLN Neg w/o ALND
Re-operative SLN
Taback, Nguyen, et al 2006[45]
• 15 pts prior Rx BCT with IBTR and prior SLN or ALND
• Preop Lymphoscintig + 11 (73%)
• 3 contralat ax, 5 ipsilat ax, 2 IM, 2 SC, 2 Intra pect
• Intraop ID 11 of 14, Mets in 3; 2 contralat ax and 1 ipsilat ax
Individual Reports
• Milardovic 2006 Epigastric node[46]
• Jackson 2006 IBTR prior neg now Pos SLN single pt[47]
• Agarwal 2005 Two pts prior BCT with ALND => IBTR => SLN contralateral +. SLN neg X 2[48]
Newman 2006[49]
• 14 LRR (10 previous ALND, 2 SLN, 2 no ax surg)
• SLN ID 90% no mets, non ipsilat drainage in 65%
Proposed
• With IBTR and prior Ax RX SLN ID (a neo-SLN) is possible ~ 70% of the time, but the potential sites are many. Therefore lymphoscintigraphy and planning SLN Bx are justified if a change in therapy would occur; e.g. 1) If a positive ipsi- or contra- lateral axillary neo-SLN would then lead to ALND. 2) If a positive neo-SLN would lead to an increase in Chemo Rx or Rad Rx. (For internal-mammary and supraclavicular nodes minimal data is available, but Chemo or Radiation are probably the only useful interventions if nodes are proven positive.)
References:
1. White EJ: "Early" Breast Cancer: Axillary Controversies. In "Unpublished." 2001:12.
2. Karalak A, Homcha-Em P: Occult axillary lymph node metastases discovered by serial section in node-negative breast cancer. J Med Assoc Thai 1999;82:1017-1019.
3. Dowlatshahi K, Fan M, Bloom KJ, et al.: Occult metastases in the sentinel lymph nodes of patients with early stage breast carcinoma: A preliminary study [see comments]. Cancer 1999;86:990-996.
4. Breslin TM, Cohen L, Sahin A, et al.: Sentinel lymph node biopsy is accurate after neoadjuvant chemotherapy for breast cancer [In Process Citation]. J Clin Oncol 2000;18:3480-3486.
5. Villa G, Gipponi M, Buffoni F, et al.: Localization of the sentinel lymph node in breast cancer by combined lymphoscintigraphy, blue dye and intraoperative gamma probe. Tumori 2000;86:297-299.
6. Langer I, Marti WR, Guller U, et al.: Axillary recurrence rate in breast cancer patients with negative sentinel lymph node (SLN) or SLN micrometastases: prospective analysis of 150 patients after SLN biopsy. Ann Surg 2005;241:152-158.